Submissions for variant NM_000335.5(SCN5A):c.2071G>A (p.Ala691Thr)

gnomAD frequency: 0.00012  dbSNP: rs199473146

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001811346	SCV000760244	uncertain significance	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 691 of the SCN5A protein (p.Ala691Thr). This variant is present in population databases (rs199473146, gnomAD 0.07%). This missense change has been observed in individual(s) with Long-QT syndrome (PMID: 15176425). ClinVar contains an entry for this variant (Variation ID: 67711). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001842309	SCV001356357	uncertain significance	Cardiac arrhythmia	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 691 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with long QT syndrome, sudden unexplained death, as well as in asymptomatic carriers (PMID: 15176425, 20566482, 34379075). This variant has been identified in 22/280226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811346	SCV002049778	uncertain significance	not provided	2021-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162455	SCV003903573	uncertain significance	Cardiovascular phenotype	2022-11-14	criteria provided, single submitter	clinical testing	The c.2071G>A (p.A691T) alteration is located in exon 14 (coding exon 13) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 2071, causing the alanine (A) at amino acid position 691 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224132	SCV003920445	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-03-30	criteria provided, single submitter	clinical testing	SCN5A NM_198056.2 exon 14 p.Ala691Thr (c.2071G>A): This variant has been reported in the literature in at least one individual affected with LQTS (Fodstad 2004 PMID:15176425). This variant is also present in 0.06% (16/25000) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/3-38639411-C-T?dataset=gnomad_r2_1) and is present in ClinVar (Variation ID:67711). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV001842309	SCV004831293	uncertain significance	Cardiac arrhythmia	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 691 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with long QT syndrome, sudden unexplained death, as well as in asymptomatic carriers (PMID: 15176425, 20566482, 34379075). This variant has been identified in 22/280226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058478	SCV000089998	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15176425). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.